Protocol for treatment of lupus nephritis

ABSTRACT

By employing a pharmacodynamic dosing regimen, the effectiveness of a protocol for treatment of a proteinuric kidney disease with voclosporin can be maximized while minimizing undesirable side effects.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Ser. No. 15/835,219 filed 7Dec. 2017 and claims benefit under 35 U.S.C. Section 119(e) of U.S.Provisional Patent Application Nos. 62/505,734, filed 12 May 2017, and62/541,612, filed 4 Aug. 2017. The contents of the above patentapplications are incorporated by reference herein in their entirety.

TECHNICAL FIELD

The invention relates to treatment of lupus nephritis and otherproteinuric kidney diseases with voclosporin. More specifically itrelates to pharmacodynamic dosing of subjects in accordance with animproved protocol for treatment.

BACKGROUND ART

Lupus nephritis (LN) one of a number of proteinuric kidney diseaseswherein an inflammation of the kidneys is caused by systemic lupuserythematosus (SLE) whereby up to 60% of SLE patients develop LN. LN isa debilitating and costly disease often leading to renal failure whichrequires dialysis, or renal transplant and often results in death.Indeed, patients with renal failure have an over 60-fold increased riskof premature death compared to SLE patients in general. A clinical signof LN is leakage of blood proteins into the urine and the disease can bediagnosed by a number of factors, including urinary protein/creatinineratio (UPCR) wherein a UPCR of greater than 0.5 mg/mg is indicative ofthe condition being in an active state. Further, certain markers in theblood can also be diagnostic—for example, complement 3 (C3), complement4 (C4) and anti-dsDNA antibodies.

The standard of care for LN has not met with a great deal of success.The standard of care is use of mycophenolate mofetil (MMF) orintravenous cyclophosphamide. With these treatments partial remissionwas found only in approximately 50% of cases and complete remission wasshown in less than 10% of the subjects. Thus, there is clearly a needfor a treatment that improves these outcomes.

Voclosporin is an analog of cyclosporin A that has been found useful fortreating autoimmune diseases and as an immunosuppressant in organtransplantation.

Mixtures of the E and Z isomers of voclosporin are described in U.S.Pat. No. 6,998,385. Mixtures with a preponderance of the E-isomer aredescribed in U.S. Pat. No. 7,332,472. The '472 patent describes a numberof indications which can be treated with the isomeric voclosporinmixture including glomerulonephritis. However, although some animalstudies are described, no protocols in humans are disclosed.

Various formulations of voclosporin mixtures are also described in U.S.Pat. Nos. 7,060,672; 7,429,562 and 7,829,533.

In October 2016, the results of a clinical study conducted on behalf ofAurinia Pharmaceuticals were published as an abstract. According to theabstract, the subjects, who were afflicted with lupus nephritis (LN),were dosed with 23.7 mg of voclosporin twice daily in combination withmycophenolate mofetil (MMF) and reducing cortical steroid dose over 24weeks for which data were presented. Entry criteria for the studyincluded determination of a urine protein creatinine ratio (UPCR) of≥1.0 mg/mg or ≥1.5 mg/mg depending on the classification of a renalbiopsy and an eGFR (estimated glomerular filtration rate) of ≥45mol/mn/1.73 m² as well as serologic evidence of LN. The results of thisprotocol showed complete remission or partial remission in a largepercentage of subjects.

In addition, it was shown that subjects who achieved a ≥25% reduction inUPCR at 8 weeks were likely to maintain benefit throughout the 24-weekor 48 week protocol.

In a news release sent by Aurinia Pharmaceuticals on 1 Mar. 2017, theresults of more extensive clinical study involving mycophenolate mofetil(MMF) and reducing corticosterone dosages, but using in addition to 23.7mg of voclosporin twice daily, a higher dose of 39.5 mg twice daily weredescribed. The results of this study showed successful complete orpartial remission in a large number of patients at 24 weeks and 48weeks. It appeared that the lower dosage of 23.7 mg twice daily (BID)was even more effective than the higher dosage of 39.5 mg twice daily(BID).

Data regarding predictability of success with respect to completeremission (CR) based on various criteria measured after 8 weeks oftreatment with 23.7 bid of Voclosporin along with MMF-1 and steroidtaper were presented by the present inventors at the 12^(th)International Congress on SLE on 27 Mar. 2017. These criteria includedUPCR (less than 25% reduction considered to show ineffectiveness) aswell as normalization of complements 3 and 4 (C3 and C4) and ofanti-dsDNA. However, the criteria for normalization of C3, C4 andanti-dsDNA were not disclosed.

An earlier study with respect to lupus treatment with cyclophosphamiderather than Voclosporin suggested normalization of C4 as a marker.Dall'Era, M. et al Arth. Care and Res. (2011) 63:351-357.

It has now been found that successful results, including a diminution inthe number and severity of side effects can be obtained by altering theprotocols disclosed in these publications by providing a pharmacodynamicdosing schedule based on individual patient responses. In addition, ithas been found that even lower dosages of voclosporin—i.e., 15.8 mg ofvoclosporin twice daily or 7.9 mg of voclosporin twice daily areeffective.

DISCLOSURE OF THE INVENTION

The present invention, thus, provides an improved protocol for treatmentof lupus nephritis and other proteinuric kidney diseases that takesadvantage of assessments of parameters associated with the response ofindividual subjects. The invention is a personalized form of a protocolfor treatment of proteinuric kidney diseases including protocols thatemploy low dosage of voclosporin. The voclosporin used is preferably amixture of greater than about 80% E isomer and less than about 20% Zisomer, and more preferably greater than about 90% E isomer and lessthan about 10% Z isomer. The protocol employs daily dosages ofvoclosporin over a projected period of 24, 48, 52 weeks or longerwherein the voclosporin is administered twice daily (BID). Suitabledosages are in increments of 7.9 mg including 39.5 mg, 31.6 mg, 23.7 mg,15.8 mg or 7.9 mg. Low dosages show superior results compared to ahigher dose of 39.5 mg each of such administrations carried out twicedaily. Doses as low as 15.8 mg or 7.9 mg twice daily are effective. Theprotocol preferably further includes administering to the subject aneffective amount of MMF and/or an effective amount of a corticosteroid,typically prednisone, in a reducing dosage level across the time periodof the study.

While it has been verified that the protocols of the invention areeffective for lupus nephritis, such results indicate the same protocolscan be used to generally treat proteinuric kidney diseases. Proteinurickidney diseases that can be treated include: Diabetic nephropathy,nephrotic syndromes (i.e. intrinsic renal failure), nephritic syndromes,toxic lesions of kidneys, glomerular diseases, such as membranousglomerulonephritis, focal segmental glomerulosclerosis (FSGS), IgAnephropathy (i.e., Berger's disease), IgM nephropathy,membranoproliferative glomerulonephritis, membranous nephropathy,minimal change disease, hypertensive nephrosclerosis and interstitialnephritis.

One of the side effects of treatment with voclosporin is an unwanteddecrease in the estimated glomerular filtration rate (eGFR). Oneinvention protocol is designed to reduce the incidence of thisundesirable side effect by adjusting the dosage in accordance with theresponse of the subject.

Thus, in one aspect, the invention is directed to a pharmacodynamicmethod to treat a proteinuric kidney disease which method comprisesadministering to a subject diagnosed with said disease a predetermineddaily dosage of effective amounts of voclosporin over a projectedtreatment period of at least 24 weeks, said pharmacodynamic methodfurther comprising:

(a) assessing the estimated Glomerular Filtration Rate (eGFR) of saidsubject at at least a first time point and a second time point ondifferent days of said treatment period, and

(b) (i) if the eGFR of said subject decreases by more than a target % tobelow a predetermined value between said first and second time points,reducing the daily dosage by increment(s) of 7.9 mg BID or stopping theadministering of voclosporin to said subject;

-   -   (ii) if the eGFR of said subject decreases by less than said        target % between said first and second time points, continuing        administering the same predetermined daily dosage of voclosporin        to said subject.

In one specific embodiment, the invention includes a pharmacodynamicmethod to treat lupus nephritis which method comprises administering toa subject diagnosed with lupus nephritis a predetermined daily dosage ofeffective amounts of voclosporin over a projected treatment period of atleast 24 weeks, said pharmacodynamic method further comprising:

(a) assessing the glomerular filtration rate (eGFR) of said subject atat least a first time point and a second time point on different days ofsaid treatment period, and

(b) (i) if the eGFR of said subject decreases by ≥30% to a value ofbelow 60 mL/min/1.73m² between said first and second time points,stopping the administering of voclosporin to said subject;

-   -   (ii) if the eGFR of said subject decreases by between 20% to 30%        to a value of below 60 ml/min/1.73m² between said first and        second time points, administering a reduced dosage of        voclosporin to said subject;    -   (iii) if the eGFR of said subject decreases by ≤20% between said        first and second time points, continuing administering the same        predetermined daily dosage of voclosporin to said subject.

The eGFR of 60 mL/min/1.73 m² noted above is typically used; however,higher values such as 90 mL/min/1.73 m² or 75 or 70 mL/min/1.73 m² orlower value such as 50 mL/min/1.73 m² or 55 mL/min/1.73 m² could also beused.

The pharmacodynamic method may employ a third time point subsequent tothe first and second time point wherein the target percentage reductionis again determined and if the percentage reduction as compared to thefirst time point is less than the target percentage, treatment may berestored, or if the percentage decrease is greater than the targetpercentage exhibited at the second time point, further reduction indosage may be indicated.

A second embodiment relates to using blood pressure as an indicatorrather than eGFR. In this second embodiment, the invention is directedto a pharmacodynamic method to treat lupus nephritis which methodcomprises administering to a subject diagnosed with lupus nephritispredetermined daily dosages of effective amounts of voclosporin over aprojected treatment period of at least 24 weeks, said pharmacodynamicmethod further comprising:

(a) measuring the blood pressure (BP) of said subject at at least afirst time point of said treatment period; and

(b) stopping the administering of voclosporin to the subject oradministering a reduced dosage of voclosporin to said subject if eithervalue of the cystolic or diastolic component of the BP of said subjectis >130/80.

In this case, an additional time point measuring BP may be employed andif both components of the BP of the subject are below 130/80, theadministration of the predetermined daily dose of voclosporin may beresumed.

Thus, blood measure elevation is an additional undesirable side-effectof treatment that can be used as a criterion for adjusting dosage.

It has also been found that the effectiveness of the protocol can beevaluated after only a portion of the treatment period has elapsed. Thiscan be done in lieu of, or in addition to, the foregoing protocol.Therefore, because it is generally undesirable to continue anineffective treatment an assessment at a time point earlier in theprotocol than the end point planned is conducted and if theeffectiveness of treatment is not confirmed, the treatment isterminated. In the present case, such termination may be helpful sincegenerally administration of an immunosuppressant is not recommendedunless some benefit is achieved.

For example, the assessment may include determining the UPCR at firstand second time points early in the protocol wherein the first point isdetermined at the outset of the protocol and stopping the administrationof voclosporin to the subject if the UPCR has not been reduced by apredetermined amount, for example by 15% or 20% or 25% or 35% at thesecond time point. The UPCR can be determined by any standard technique,e.g., using first morning void or a 24 hour urine sample. Thisevaluation may be supplemented or substituted by evaluation of theconcentration of C3 and C4 in the blood. Failure of the treatment toresult in normalizing C3/C4 concentration indicates lack of success. Therule for stopping treatment if a combination of these factors isemployed is that treatment will be stopped if neither criterion forsuccess is met—i.e. the subject shows no satisfactory reduction in UPCRat the second time point and no normalization of C3/C4 at the secondtime point. In the alternative, either criterion could be used alone.

Alternatively, if it appears that the subject is in complete remission,it may be unnecessary to continue treatment.

In any of the protocols above, preferably, a dosage of MMF and areducing dosage of corticosteroid is also administered during thetreatment period. Typically, MMF is administered at the level of 2 gramsdaily and oral corticosteroids are administered in daily dosagesdiminishing from 20-25 mg daily to 2.5 mg daily over a period of 16weeks. The reduced dosages then continue throughout the study. Theseprotocols are shown in FIG. 1.

In all cases, subjects who would be amenable to this treatment areidentified by screening said subject prior to conducting said method onsaid subject by:

(a) determining that the urine protein creatinine ratio (UPCR) of saidsubject is ≥1.5 mg/mg or ≥1 mg/mg depending on renal biopsy aspreferably measured by first morning void; and

(b) determining said subject has an eGFR as measured by the ChronicKidney Disease Epidemiology Collaboration equation (CKD-EPI) of ≥45mL/min/1.73 m²or any other suitable method such as the Modification ofDiet in Renal Disease (MDRD) Study equation. If the determinations ofsubparagraphs (a) and (b) are positive, the subject is consideredsuitable for subjection to the protocol.

In addition, lowered levels of voclosporin dosage have been shown to beeffective.

Thus, in another aspect, the invention is directed to a method to treatlupus nephritis which method comprises administering to a subjectdiagnosed with lupus nephritis a predetermined daily dosage of effectiveamounts of voclosporin wherein said effective amount is either 15.8 mgBID or 7.9 mg BID. Surprisingly, it has been found that these lowerdosages are effective in a majority of patients, especially if thetreatment is prolonged beyond 24 weeks. A dosage of 31.6 mg BID (4capsules) could also be employed. Pharmacodynamic dosing can be appliedin these instances as well.

It is also advantageous and part of the invention to evaluate a subjectwho has been treated with the protocol at the end of the treatmentperiod to determine whether a complete or partial remission hasoccurred. Further evaluations are included at a time subsequent totermination of the treatment to assess whether the remission achievedaccording to the measurement at the end of the treatment is beingmaintained. Such evaluation may also be done at intermediate timesduring treatment to determine whether dosage can be reduced. In anexemplary embodiment used simply for illustration a dosage of 23.6 mgvoclosporin BID may be reduced to 15.8 mg or 7.9 mg BID based on suchresults.

The evaluation for effectiveness can be based on the protein/creatinineratio in urine (UPCR) where a ratio of ≤0.5 mg/mg indicates completeresponse; alternatively, or in addition, an eGFR of ≥60 mL/min/1.73 m²or no decrease from baseline and eGFR of ≥20% is shown. Otherindications of complete response include lack of need for rescuemedications such as intravenous steroids, cyclophosphamide or a need for≤10 mg prednisone for more than three consecutive days or more thanseven days total. These evaluations may be performed at any point in thetreatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows graphically the design of a protocol for treatment of lupusnephritis with voclosporin upon which the pharmacodynamic treatment ofthe invention is superimposed.

FIG. 2 is a bar graph showing a comparison of complete remission (CR) at48 weeks and partial remission (PR) at 48 weeks for low dose as comparedto high dose of voclosporin (VCS). The PR percentages include the CRpercentages.

MODES OF CARRYING OUT THE INVENTION

As noted above, the pharmacodynamic protocol of the invention relates toadjustment of administration of voclosporin depending on certainphysiological indicators of the subjects. As further noted, thevoclosporin administration is preferably conducted with a background ofadministration of MMF and of corticosteroids.

In general, the treatment protocols on which the invention is based showdramatically better results than the current standard of care—the rateof complete remission is almost 50% as compared to much lower levelsachieved using the current standard of care treatment and the rate ofpartial remission after 48 weeks is even higher, wherein this rate (PR)includes the subjects with complete remission (CR). As shown below, alower dosage of voclosporin is more effective than a higher dose in acomparable protocol wherein complete remission was obtained in 40% ofthe subjects at the higher dosage as opposed to 49% of the subjects inthe lower dose group.

Critical to the present invention is pharmacodynamic administration ofthe voclosporin component. This pharmacodynamic administration isessential as the effects of this drug may be too intense and/or haveundesirable side effects or the results may indicate lack ofeffectiveness and thus the dosage is reduced or interrupted to permithomeostasis to reestablish a suitable set of physiological parameters.

The protocols are designed to cover treatment periods of at least 24weeks and may extend for longer periods of time, for example 48 weeks or52 weeks. The regimens involve daily dosages of the voclosporincomponent, typically twice daily, although alternative frequencies couldbe employed, such as once a day, three times a day or four times a daybased on reactions of the patient and convenience. As an illustration,the protocol will be described below in terms of a 23.7 mg twice daily(BID) dosage; of course if the voclosporin preparation is administeredfour times daily, the dosage would be cut in half for eachadministration and if the administration were only once per day, thedosage for the once a day administration would be double the 23.7 mgadministered BID.

In addition, as to the pharmacodynamic protocols of the invention, thedosages may be any combination of the 7.9 mg basic units, and thus canbe 7.9 mg, 15.8 mg, 31.6 mg, or 39.5 mg, as well as the exemplified 23.7mg.

The dosage indicated, for example 23.7 mg, (or any other specified dose)is subject to slight variations, typically ±10% or, alternatively, for23.7 mg specified between 21 mg and 26 mg BID. This is due toinconsistencies in pharmaceutical manufacture and the ideal dosage isthe specified dose—i.e., for example, 23.7 mg BID. Comparable variationsapplied to the alternative dosages, and to the differential adjustment.

Adjustment Based on eGFR:

One critical parameter used to assess the desirability of dosagereduction is the eGFR using the CKD-EP1 formula or other appropriatemethod. Chronic kidney disease is defined as eGFR as ≤60 mL/min/1.73 m²for ≥three months with or without kidney damage. As noted above, afurther decrease in eGFR is a negative side effect that may occur duringtreatment. If the decrease is too severe, the protocol should be alteredin accordance with the prescription of the invention. Typically, abaseline value of the eGFR is established either at the beginning of theprotocol or at some “first time point” during the protocol. If thedecrease is greater than a target percentage, which is typically between20%-45% as compared to the first time point, a reduction in dosage isindicated, including a reduction to zero or stopping treatment. If thedecrease is less than that target percentage maintenance of treatment atthe same level as indicated. In addition to an indication that treatmentshould be reduced or terminated based on the eGFR reduction, reductionbelow a certain value is also indicative of a need to modify thetreatment. This predetermined value is typically in the range of 50-90mL/min/1.73 m².

As stated above, a baseline value for eGFR is established at the outsetof the treatment or during treatment. This is typically done on thefirst day of the treatment before any administration of the drugs in theprotocol. This baseline is used as a criterion for adjusting dosage.However, a first time point could be established at any arbitrarilyselected time during the protocol.

In one exemplary protocol, at a second time point subsequent to thefirst which can be on any day of the treatment, a subject with ≥30%decrease in eGFR from the baseline to <60 ml/min/1.73 m² (or, in somecases, a higher cut off) should have the treatment interrupted until arepeat test can be performed, but if the decrease is confirmed and notdue to contributing factors (such as a high baseline eGFR, the additionor modification of non-steroidal anti-inflammatory drugs, angiotensinconverting enzyme inhibitors, angiotensin 2 inhibitor blockers, or aconcurrent state of dehydration, etc.), the treatment should be withhelduntil a third time point determination typically within 48 hours. If the≥30% decrease is not maintained, treatment is restored to two-thirds orone-third of the original dosage and increased as tolerated to the 23.7mg level BID.

For convenience, the 23.7 mg administration is administered orally inthe form of three capsules containing 7.9 mg each. Thus, it is easy toprovide two-thirds of the standard dosage by administering at any giventime only two of the three capsules.

With regard to the second time point, in this exemplary protocol asubject having a decrease of ≥20% in eGFR to ≤60 mL/min/1.73 m² but adecrease of less than 30% reduction as compared to baseline, thetreatment is not interrupted but the dosage is reduced. Reduction inincrements of 7.9 mg is preferred. Again, assessment at an additionaltime point at any subsequent day during the treatment showing baselinevalues are restored indicates that the original dosage level of 23.7 mgBID can be resumed.

Adjustment Based on Blood Pressure

An alternative parameter that can be used to determine pharmacodynamicdosage is blood pressure. As voclosporin may increase blood pressure toundesirable levels, at any point during the treatment period if eithercomponent of the blood pressure i.e. the cystolic or diastolic pressureof the subject is ≥130/80, the treatment should be reduced, preferablyby increments of 7.9 mg. At a later time point if both components of theblood pressure are below 130/80, the treatment can be restored to theoriginal level.

Adjustment Based on UPCR Reduction and/or C3/C4 Normalization

Suitable criteria for early evaluation of the probability ofsuccess—i.e. complete or partial remission by the end of a plannedprotocol, have been identified which permit discontinuation of thetreatment earlier than the end point if it is highly unlikely that thesubject will benefit from continuing on the dosage schedule. Thesecriteria are reduction in UPCR and normalization of C3/C4. These can beused in combination or in the alternative. It has been found that adetermination early in a 24-week or 48 week protocol of probable successcan be used to determine whether treatment with voclosporin shouldcontinue; such findings are applicable to protocols of any substantiallength. By way of illustration, if the UPCR has not been reduced by asatisfactory amount early in the regimen or if C3/C4 has not beennormalized early in the regimen, one might conclude that the chances ofimprovement over an extended treatment period are diminished.Application of these criteria in an exemplary trial is shown in detailin Example 3.

However, a rule for stopping treatment is based either on UPCR reductionor C3/C4 normalization taken alone or in combination. If the combinationis used, then failure with respect to both criteria would dictatetermination of treatment. Decision would be based on the values of thesensitivity, specificity and positive and negative predictive valuesshown in the tables set forth in Example 3. These terms are defined inthe Example.

As an illustration only, such determination can be made at approximately8 weeks subsequent to the beginning of the regimen; a time frame of 6-10weeks could be employed for the approximation of 8 weeks. If a decreaseof, for example, ≥25% of UPCR is not achieved, it appears unlikely thesubject will benefit from further treatment and the protocol is stopped.As shown in the Example, this can be supplemented with evaluation ofC3/C4 normalization—if this is done, it is desirable that bothdeterminations be made at the same early time point.

Auxiliary Therapeutics

The voclosporin treatment of the invention is supplemented with MMF andreduced amounts of corticosteroids.

For example, with respect to corticosteroids, subjects who weigh 45 kgor more may receive 0.5 grams of methylprednisolone on days 1 and 2 ofthe study intravenously and then beginning on day 3, oral corticosteroidtherapy. Subjects weighing ≤45 kg receive only half these dosages.

For oral prednisone, the starting dosage for oral administration is 20mg/day for subjects <45 kg and 25 mg/day for subjects who weigh ≥45 kg.The dosage is reduced according to the protocol shown in Table 1.

TABLE 1 Dosing Schedule for IV Methylprednisolone and Daily OralPrednisone (mg) In Case of Prior IV Steroids Subjects < 45 kg Subjects ≥45 kg During Screening (Pre-randomization) Weeks 1-2⁽¹⁾ Days 1-2⁽²⁾ 0.25g (IV) 0.5 g (IV) 1 g minus prior IV steroids mg or (0.5 g minus priorIV steroids mg for subjects who weigh <45 kg)⁽³⁾ Days 3-13 20 mg (oral)25 mg (oral) Week 2 (Day 14) 15 mg (oral) 20 mg (oral) Week 4 (Day 28)10 mg (oral) 15 mg (oral) Week 6 (Day 42)⁽⁴⁾ 10 mg (oral) 10 mg (oral)Week 8 (Day 56) 5 mg (oral) 5 mg (oral) Week 12 (Day 84) 5 mg (oral) 5mg (oral) Week 16 (Day 112) 2.5 mg (oral) 2.5 mg (oral) ⁽¹⁾Day 0-13:Oral steroids dosed according to subject weight and then taperedbeginning at Day 14. ⁽²⁾Oral corticosteroids may be commenced on Days 1or 2 if corticosteroids are administered during screening. ⁽³⁾It isrecognized that dosing with IV methylprednisolone as described inSection 7.2.2.2. Corticosteroids may not be in the subject's bestinterest if they have already received therapy within the 3 months priorto screening. In this case, the Investigator may be permitted to omitthe administration of further IV methylprednisolone but only afterdiscussion with the Medical Monitor. ⁽⁴⁾Week 6 is not a scheduled studyvisit, a phone call can be performed to decide further tapering forsubjects. Notes: Oral prednisone taper should be done within ±3 days ofspecified timeframe. When clinically indicated, subjects are allowed tobe completely titrated off of oral corticosteroids. Abbreviation: IV =Intravenous.

In contrast to the reducing dose of corticosteroid, the same dose of MMFis maintained throughout the study at a twice daily dosage before mealswith a glass of water. Typically, each individual dose is one gramresulting in a total dosage of two grams per day although in thealternative, the subject may be administered 500 mg four times daily.

Low Dosage

In addition to the above-described pharmacodynamic protocols, applicantshave found that a substantially lower dosage than expected is effectivein large numbers of subjects such that a method to treat lupus nephritisin subjects either with or without pharmacodynamic adjustments can bebased on a dosage level of either 15.8 mg BID or 7.9 mg BID. Theincrements of 7.9 mg are dictated by the availability of capsulescontaining the 7.9 mg dosage level which provides a convenient platformfor dosage alterations.

One additional aspect of the invention is therefore a method to treatlupus nephritis wherein either a logically adjusted dosage or a constantdosage of either 15.8 mg BID or 7.9 mg BID is employed. In theseprotocols, as would be the case for higher dosages of voclosporin, theabove described background administration of MMF and corticosteroids isincluded in the protocol.

General Factors

In all cases, the subjects are evaluated for success of the treatmentboth on the completion of the treatment and at extended periodsthereafter. Typical treatment periods are at least 24 weeks, butpreferably 48 weeks or more. Reevaluation after the termination of thetreatment period over a period of 1-2 weeks or longer is also employed.Subjects are evaluated for complete or partial remission. Completeremission (CR) is defined as: Confirmed protein/creatinine ratio of ≤0.5mg/mg, and eGFR≥60 mL/min/1.73 m² or no confirmed decrease from baselinein eGFR of ≥20%. Partial remission is defined as: 50% reduction in UPCRfrom baseline.

By establishing a pharmacodynamic dosing regimen, the effectiveness ofthe protocol in treatment of lupus nephritis can be maximized whileminimizing undesirable side effects.

The length of the treatment protocol in all cases will vary from atleast 8 weeks to for example 12, 16, 24 and 48 weeks or 52 weeks or evenlonger, up to 60 weeks including stopping points between the levelsmentioned. For example, a treatment protocol of 10 or 11 or 15 or 20 or29 or 31 or 36 or 43 or 51 or 55 weeks could be employed and is withinthe scope of the invention. The evaluation described above is conductedat the end of the protocol as well as at a suitable time period ormultiple time periods thereafter. These time periods are generally 1-2weeks to 4-5 months subsequent to terminating the dosage and interveningat time intervals are included within the scope of the invention aswell.

This statement regarding time intervals applies to the inventionpharmacodynamic treatment protocols, regardless of base dosage levels.

The following examples are to illustrate, not to limit the invention.

EXAMPLE 1 48 Week Study of LN Treatment

The subjects enrolled in the study were divided into three groups, 88subjects are in a control group who were administered 2 g MMF daily aswell as oral corticosteroids—i.e., prednisone in a tapering dosage showngraphically in FIG. 1—beginning at 20-25 mg daily reduced graduallyafter the 12^(th) week to 2.5 mg daily. (Some subjects received lowerdoses of MMF due to gastrointestinal problems). 89 subjects in the lowdosage group received this background treatment, but in addition wereadministered three capsules containing 7.9 mg (i.e. 23.7 mg) ofvoclosporin each twice daily. The voclosporin used in this studycomprised greater than 90% E isomer. A third group which was comprisedof 88 subjects received a similar background treatment but in additionwere dosed with five 7.9 mg capsules i.e. 39.5 mg twice daily. The studywas conducted over a period of 48 weeks and safety was evaluated at 24weeks.

Subjects were screened prior to admission to the study by (a)determining that the urine protein creatinine ratio (UPCR) as >1.5 mg/mgas measured by first morning void, and (b) that the eGFR as measured byChronic Kidney Disease Epidemiology Collaboration equation (CKD-EP1)of >45 ml/min/1.73 m². Subjects were assessed after 24 weeks and 48weeks as well as a subsequent evaluation at 50 weeks.

As shown in FIG. 2, the low dosage administration achieved betterresults than administration of voclosporin at higher dosages. After 48weeks of treatment, 49% of low dosage subjects showed complete remissionat 48 weeks, compared to 40% of high dosage subjects. In the same study,but after 24 weeks of treatment, 32.6% of low dosage patients, but only27% of high dosage patients showed complete remission (CR) compared to19.3% of controls. At 24 weeks, 70% of low dosage patients and 66% ofhigh dosage patients showed partial remission (PR) compared to 49% ofcontrols.

CR in this example is a composite end-point which includes efficacy,safety and low-dose steroids: UPCR≤0.5 mg/mg (confirmed); eGFR>60ml/min/1.73 m2 or within 20% of baseline; steroids≤10 mg/day; noadministration of rescue medication.

PR is a composite end-point that includes safety and efficacy: UPCRreduction of 50% from baseline and no use of rescue medication

To determine the efficacy of the pharmacodynamic protocol wherein dosageis reduced or stopped according to the presence or absence of indicatorsof the decrease in eGFR experienced as a side effect, these three groupsof patients were assessed after 24 weeks and 48 weeks of treatment withrespect to whether treatment was altered according to the inventionprotocol. In all three groups, the patients were evaluated according tothe criteria set forth in the exemplary protocol above—i.e., wherein theeGFR of each patient was measured immediately prior to administering thefirst dose of voclosporin and at a second time point at least a daylater and

-   -   (i) if the eGFR of said subject decreased by ≥30% to a value of        below 60 mL/min/1.73 m² between said first and second time        points, stopping the administering of Voclosporin or reducing        dosage thereof to said subject;    -   (ii) if the eGFR of said subject decreased by between 20% to 30%        to a value of below 60 ml/min/1.73 m² between said first and        second time points, administering a reduced dosage of        voclosporin to said subject;    -   (iii) if the eGFR of said subject decreased by ≤20% between said        first and second time points, continuing administering the same        predetermined daily dosage of voclosporin to said subject.

The results are shown in Tables 2 and 3 below. Table 2 shows percentageswith complete remission (CR) or partial remission (PR) after 24 weeksand Table 3 shows these values after 48 weeks for patients that had nodose reduction and those who did have dose reduction.

TABLE 2 Patients with a No Dose Reductions (24 weeks): Patients PatientsPatients Patient with no Dose with CR at with PR at number Reduction 24weeks 24 weeks Group (n) n(%) n(%) n(%) Placebo 88 77 (87.5) 14 (18.2)36 (46.8) Low Dose 89 50 (56.2) 15 (30.0) 34 (68.0) High Dose 88 41(46.6) 11 (26.8) 24 (58.5) Patients with Dose Reductions(pharmacodynamically dosed): Patients Patients Patients Patient withDose with CR at with PR at number Reduction 24 weeks 24 weeks Group (n)n(%) n(%) n(%) Placebo 88 11 (12.5)  3 (27.3)  7 (63.6) Low Dose 89 39(43.8) 14 (35.9) 28 (71.8) High Dose 88 47 (53.4) 13 (27.7) 34 (72.3)

TABLE 3 Patients with No Dose Reductions (48 weeks): Patients PatientsPatients Patient with no Dose with CR at with PR at number Reduction 48weeks 48 weeks Group (n) n(%) n(%) n(%) Placebo 88 74 (84.1) 18 (24.3)38 (51.4) Low Dose 89 43 (48.3) 20 (46.5) 26 (60.5) High Dose 88 35(39.8) 11 (31.4) 22 (62.9) Patients with Dose Reductions(pharmacodynamically dosed): Patients Patients Patients Patient withDose with CR at with PR at number Reduction 48 weeks 48 weeks Group (n)n(%) n(%) n(%) Placebo 88 14 (15.9)  3 (21.4)  4 (28.6) Low Dose 89 46(51.7) 24 (52.2) 35 (76.1) High Dose 88 53 (60.2) 24 (45.3) 41 (77.4)

In this study, CR was defined as a composite of UPCR≤0.5 mg/mg; eGFR>60mL/min/1.73 m² or within 20% of baseline, steroids at ≤10 mg/day and noadministration of rescue medication. PR is defined as UPCR reduction of50% from baseline and no use of rescue medication.

As shown in Table 2, 12.5% of patients on placebo, 43.8% of patients onlow dose and 53.4% of patients on high dose voclosporin underwent dosereduction during the treatment. The percentage of patients with completeresponse after 24 weeks was not affected in either dosage groups by thepharmacodynamic dosage and the percentage with partial response was alsoroughly the same, although with the high dose group, the percentage withpartial reduction improved. Table 3 shows similar results at 48 weeks,although a higher percentage of patients were subjected to dosereduction. Again, no drastic effect on the overall response wasexhibited.

EXAMPLE 2 Low Dosage Protocol

In the course of clinical studies similar to those in Example 1, it wasobserved that a substantial portion of subjects showed substantialremission at a dosage reduced almost immediately to 15.8 mg voclosporinadministered twice daily (BID). Accordingly, applicants have analyzedthese data and have concluded that a dosage protocol providing 15.8 mgor 7.9 mg voclosporin BID is effective with or without thepharmacodynamic aspects of the protocol.

As the capsules contain 7.9 mg voclosporin, 1 cap represents 7.9 mgvoclosporin, 2 caps represent 15.8 mg voclosporin and 3 caps represent23.7 mg voclosporin, etc. Substantial numbers of subjects showedcomplete or partial remission even when the dosage was lowered to 7.9 mgvoclosporin BID quite early in the treatment and similar results wereobtained for administration of 15.8 mg BID.

EXAMPLE 3 Predictability Based on Early Responses

In the study reported in Example 1, the predictability of outcomes basedon markers at early time points were determined. These results are shownin Tables 4-12.

In the study described in Example 1, data were obtained to ascertainwhether markers evaluated after various time-points during treatmentwould predict an ultimate favorable outcome or show that continuingtreatment was likely to be futile. This is important because it isundesirable to subject a patient to unnecessary treatment, even if thetreatment is relatively safe. These data are shown in the tables below.

Based on these data, the sensitivity and specificity of the evaluationof each marker and their counterparts positive predictive value andnegative predictive value were determined with respect to whether thepatient would or would not show partial remission (PR) after 48 weeks ofthe treatment protocol. PR is defined as at least 50% reduction inproteinuria (i.e. UPCR). This would also include subjects who showedcomplete remission (CR).

Sensitivity is defined as the probability that a subject showing PR at48 weeks would have shown a favorable result with regard to the markerat the designated early time point. In the tables below, this is theratio of the number of subjects with favorable marker results (earlydrop or normalization) to the total subjects with 48 week PR.

Specificity is defined as the probability that a subject not showing PRat 48 weeks would have shown an unfavorable result with regard to themarker at the designated early time point. In the tables below, this isthe ratio of the number of subjects with unfavorable marker results (noearly drop or no normalization) to the total subjects with no 48 weekPR.

Positive predictive value is defined as the probability that a subjectshowing a favorable result with respect to the marker at an earlier timepoint would show PR at 48 weeks. In the tables below, this is the ratioof the number of subjects with favorable marker results who have 48 weekPR to those with favorable marker results (early reduction or yescolumn).

Negative predictive value is defined as the probability that a subjectshowing an unfavorable result with respect to the marker at an earliertime point would not show PR at 48 weeks. In the tables below, this isthe ratio of the number of subjects with unfavorable marker results whohave no PR at 48 weeks to the total subjects with unfavorable markerresults (no early reduction or no column).

An ideal marker would show a value of 100 for all of these, but this isgenerally unattainable. As high as possible value is desirable.

Based on the results in these tables, the protocol will be designed tostop treatment at an earlier time point when the parameters set forthabove are the most favorable, but at a reasonable time before the 48week end point. (Obviously the closer to the end point, the morefavorable the indicators become, but the advantage to stopping treatmentis correspondingly reduced).

TABLE 4 Early 15% reduction in UPCR Week 48 Partial No Week 48 RemissionPartial Remission Early Positive Negative No Early No Early ReductionPredictive Predictive Week Treatment Group Early Drop Drop Early DropDrop Yes No Sensitivity Specificity Value Value 2 Placebo 27 15 19 25 4640 64.3 56.8 58.7 62.5 Voclosporin 45 16 10 14 55 30 73.8 58.3 81.8 46.723.7 mg BID Voclosporin 39 21 15 9 54 30 65.0 37.5 72.2 30.0 39.5 mg BID4 Placebo 36 5 18 23 54 28 87.8 56.1 66.7 82.1 Voclosporin 50 9 12 11 6220 84.7 47.8 80.6 55.0 23.7 mg BID Voclosporin 49 12 16 5 65 17 80.323.8 75.4 29.4 39.5 mg BID 6 Placebo 35 7 22 17 57 24 83.3 43.6 61.470.8 Voclosporin 53 6 12 6 65 12 89.8 33.3 81.5 50.0 23.7 mg BIDVoclosporin 53 10 16 4 69 14 84.1 20.0 76.8 28.6 39.5 mg BID 8 Placebo38 4 22 18 60 22 90.5 45.0 63.3 81.8 Voclosporin 55 5 12 7 67 12 91.736.8 82.1 58.3 23.7 mg BID Voclosporin 56 5 17 4 73 9 91.8 19.0 76.744.4 39.5 mg BID 12 Placebo 39 3 19 21 58 24 92.9 52.5 67.2 87.5Voclosporin 59 2 15 4 74 6 96.7 21.1 79.7 66.7 23.7 mg BID Voclosporin57 5 14 4 71 9 91.9 22.2 80.3 44.4 39.5 mg BID 16 Placebo 39 3 19 20 5823 92.9 51.3 67.2 87.0 Voclosporin 58 3 13 5 71 8 95.1 27.8 81.7 62.523.7 mg BID Voclosporin 57 6 15 5 72 11 90.5 25.0 79.2 45.5 39.5 mg BID20 Placebo 38 4 21 16 59 20 90.5 43.2 64.4 80.0 Voclosporin 60 0 13 3 733 100.0 18.8 82.2 100.0 23.7 mg BID Voclosporin 58 4 15 5 73 9 93.5 25.079.5 55.6 39.5 mg BID 24 Placebo 37 3 18 17 55 20 92.5 48.6 67.3 85.0Voclosporin 60 0 12 2 72 2 100.0 14.3 83.3 100.0 23.7 mg BID Voclosporin57 5 14 5 71 10 91.9 26.3 80.3 50.0 39.5 mg BID 26 Placebo 36 3 16 14 5217 92.3 46.7 69.2 82.4 Voclosporin 55 0 9 3 64 3 100.0 25.0 85.9 100.023.7 mg BID Voclosporin 61 0 12 4 73 4 100.0 25.0 83.6 100.0 39.5 mg BID36 Placebo 41 1 18 13 59 14 97.6 41.9 69.5 92.9 Voclosporin 60 1 10 3 704 98.4 23.1 85.7 75.0 23.7 mg BID Voclosporin 62 1 12 6 74 7 98.4 33.383.8 85.7 39.5 mg BID 48 Placebo 37 1 10 16 47 17 97.4 61.5 78.7 94.1Voclosporin 58 0 9 2 67 2 100.0 18.2 86.6 100.0 23.7 mg BID Voclosporin61 0 10 6 71 6 100.0 37.5 85.9 100.0 39.5 mg BID

TABLE 5 Early 20% reduction in UPCR Week 48 Partial No Week 48 RemissionPartial Remission Early Positive Negative No Early No Early ReductionPredictive Predictive Week Treatment Group Early Drop Drop Early DropDrop Yes No Sensitivity Specificity Value Value 2 Placebo 24 18 15 29 3947 57.1 65.9 61.5 61.7 Voclosporin 44 17 8 16 52 33 72.1 66.7 84.6 48.523.7 mg BID Voclosporin 36 24 14 10 50 34 60.0 41.7 72.0 29.4 39.5 mgBID 4 Placebo 32 9 13 28 45 37 78.0 68.3 71.1 75.7 Voclosporin 49 10 1211 61 21 83.1 47.8 80.3 52.4 23.7 mg BID Voclosporin 47 14 16 5 63 1977.0 23.8 74.6 26.3 39.5 mg BID 6 Placebo 34 8 22 17 56 25 81.0 43.660.7 68.0 Voclosporin 53 6 11 7 64 13 89.8 38.9 82.8 53.8 23.7 mg BIDVoclosporin 53 10 15 5 68 15 84.1 25.0 77.9 33.3 39.5 mg BID 8 Placebo38 4 19 21 57 25 90.5 52.5 66.7 84.0 Voclosporin 55 5 11 8 66 13 91.783.3 61.5 23.7 mg BID Voclosporin 55 6 17 4 72 10 90.2 19.0 76.4 40.039.5 mg BID 12 Placebo 38 4 19 21 57 25 90.5 52.5 66.7 84.0 Voclosporin59 2 14 5 73 7 96.7 26.3 80.8 71.4 23.7 mg BID Voclosporin 57 5 14 4 719 91.9 22.2 80.3 44.4 39.5 mg BID 16 Placebo 39 3 17 22 56 25 92.9 56.469.6 88.0 Voclosporin 58 3 12 6 70 9 95.1 33.3 82.9 66.7 23.7 mg BIDVoclosporin 57 6 15 5 72 11 90.5 25.0 79.2 45.5 39.5 mg BID 20 Placebo38 4 20 17 58 21 90.5 45.9 65.5 81.0 Voclosporin 60 0 12 4 72 4 100.025.0 83.3 100.0 23.7 mg BID Voclosporin 58 4 15 5 73 9 93.5 25.0 79.555.6 39.5 mg BID 24 Placebo 37 3 16 19 53 22 92.5 54.3 69.8 86.4Voclosporin 59 1 11 3 70 4 98.3 21.4 84.3 75.0 23.7 mg BID Voclosporin56 6 14 5 70 11 90.3 26.3 80.0 45.5 39.5 mg BID 26 Placebo 36 3 15 15 5118 92.3 50.0 70.6 83.3 Voclosporin 55 0 9 3 64 3 100.0 25.0 85.9 100.023.7 mg BID Voclosporin 61 0 12 4 73 4 100.0 25.0 83.6 100.0 39.5 mg BID36 Placebo 41 1 16 15 57 16 97.6 48.4 71.9 93.8 Voclosporin 60 1 10 3 704 98.4 23.1 85.7 75.0 23.7 mg BID Voclosporin 61 2 12 6 73 8 96.8 33.383.6 75.0 39.5 mg BID 48 Placebo 37 1 9 17 46 18 97.4 65.4 80.4 94.4Voclosporin 58 0 9 2 67 2 100.0 18.2 86.6 100.0 23.7 mg BID Voclosporin61 0 10 6 71 6 100.0 37.5 85.9 100.0 39.5 mg BID

TABLE 6 Early 25% reduction in UPCR Week 48 Partial No Week 48 RemissionPartial Remission Early Positive Negative No Early No Early ReductionPredictive Predictive Week Treatment Group Early Drop Drop Early DropDrop Yes No Sensitivity Specificity Value Value 2 Placebo 18 24 15 29 3353 42.9 65.9 54.5 54.7 Voclosporin 39 22 8 16 47 38 63.9 66.7 83.0 42.123.7 mg BID Voclosporin 33 27 14 10 47 37 55.0 41.7 70.2 27.0 39.5 mgBID 4 Placebo 30 11 11 30 41 41 73.2 73.2 73.2 73.2 Voclosporin 48 11 1211 60 22 81.4 47.8 80.0 50.0 23.7 mg BID Voclosporin 45 16 16 5 61 2173.8 23.8 73.8 23.8 39.5 mg BID 6 Placebo 33 9 20 19 53 28 78.6 48.762.3 67.9 Voclosporin 51 8 10 8 61 16 86.4 44.4 83.6 50.0 23.7 mg BIDVoclosporin 49 14 15 5 64 19 77.8 25.0 76.6 26.3 39.5 mg BID 8 Placebo35 7 17 23 52 30 83.3 57.5 67.3 76.7 Voclosporin 54 6 10 9 64 15 90.047.4 84.4 60.0 23.7 mg BID Voclosporin 55 6 17 4 72 10 90.2 19.0 76.440.0 39.5 mg BID 12 Placebo 37 5 17 23 54 28 88.1 57.5 68.5 82.1Voclosporin 57 4 13 6 70 10 93.4 31.6 81.4 60.0 23.7 mg BID Voclosporin57 5 14 4 71 9 91.9 22.2 80.3 44.4 39.5 mg BID 16 Placebo 39 3 17 22 5625 92.9 56.4 69.6 88.0 Voclosporin 58 3 11 7 69 10 95.1 38.9 84.1 70.023.7 mg BID Voclosporin 56 7 14 6 70 13 88.9 30.0 80.0 46.2 39.5 mg BID20 Placebo 38 4 17 20 55 24 90.5 54.1 69.1 83.3 Voclosporin 59 1 11 5 706 98.3 31.3 84.3 83.3 23.7 mg BID Voclosporin 58 4 15 5 73 9 93.5 25.079.5 55.6 39.5 mg BID 24 Placebo 37 3 13 22 50 25 92.5 62.9 74.0 88.0Voclosporin 59 1 11 3 70 4 98.3 21.4 84.3 75.0 23.7 mg BID Voclosporin55 7 12 7 67 14 88.7 36.8 82.1 50.0 39.5 mg BID 26 Placebo 36 3 14 16 5019 92.3 53.3 72.0 84.2 Voclosporin 55 0 8 4 63 4 100.0 33.3 87.3 100.023.7 mg BID Voclosporin 60 1 12 4 72 5 98.4 25.0 83.3 80.0 39.5 mg BID36 Placebo 41 1 16 15 57 16 97.6 48.4 71.9 93.8 Voclosporin 60 1 10 3 704 98.4 23.1 85.7 75.0 23.7 mg BID Voclosporin 61 2 12 6 73 8 96.8 33.383.6 75.0 39.5 mg BID 48 Placebo 37 1 9 17 46 18 97.4 65.4 80.4 94.4Voclosporin 58 0 9 2 67 2 100.0 18.2 86.6 100.0 23.7 mg BID Voclosporin61 0 7 9 68 9 100.0 56.3 89.7 100.0 39.5 mg BID

TABLE 7 Early 30% reduction in UPCR Week 48 Partial No Week 48 RemissionPartial Remission Early Positive Negative No Early No Early ReductionPredictive Predictive Week Treatment Group Early Drop Drop Early DropDrop Yes No Sensitivity Specificity Value Value 2 Placebo 14 28 13 31 2759 33.3 70.5 51.9 52.5 Voclosporin 37 24 6 18 43 42 60.7 75.0 86.0 42.923.7 mg BID Voclosporin 31 29 11 13 42 42 51.7 54.2 73.8 31.0 39.5 mgBID 4 Placebo 27 14 10 31 37 45 65.9 75.6 73.0 68.9 Voclosporin 47 12 1112 58 24 79.7 52.2 81.0 50.0 23.7 mg BID Voclosporin 45 16 15 6 60 2273.8 28.6 75.0 27.3 39.5 mg BID 6 Placebo 32 10 16 23 48 33 76.2 59.066.7 69.7 Voclosporin 49 10 10 8 59 18 83.1 44.4 83.1 44.4 23.7 mg BIDVoclosporin 47 16 15 5 62 21 74.6 25.0 75.8 23.8 39.5 mg BID 8 Placebo34 8 15 25 49 33 81.0 62.5 69.4 75.8 Voclosporin 53 7 10 9 63 16 88.347.4 84.1 56.3 23.7 mg BID Voclosporin 54 7 17 4 71 11 88.5 19.0 76.136.4 39.5 mg BID 12 Placebo 36 6 16 24 52 30 85.7 60.0 69.2 80.0Voclosporin 56 5 12 7 68 12 91.8 36.8 82.4 58.3 23.7 mg BID Voclosporin55 7 14 4 69 11 88.7 22.2 79.7 36.4 39.5 mg BID 16 Placebo 39 3 16 23 5526 92.9 59.0 70.9 88.5 Voclosporin 58 3 11 7 69 10 95.1 38.9 84.1 70.023.7 mg BID Voclosporin 55 8 13 7 68 15 87.3 35.0 80.9 46.7 39.5 mg BID20 Placebo 38 4 16 21 54 25 90.5 56.8 70.4 84.0 Voclosporin 57 3 9 7 6610 95.0 43.8 86.4 70.0 23.7 mg BID Voclosporin 57 5 15 5 72 10 91.9 25.079.2 50.0 39.5 mg BID 24 Placebo 37 3 11 24 48 27 92.5 68.6 77.1 88.9Voclosporin 59 1 11 3 70 4 98.3 21.4 84.3 75.0 23.7 mg BID Voclosporin53 9 12 7 65 16 85.5 36.8 81.5 43.8 39.5 mg BID 26 Placebo 34 5 12 18 4623 87.2 60.0 73.9 78.3 Voclosporin 54 1 7 5 61 6 98.2 41.7 88.5 83.323.7 mg BID Voclosporin 58 3 11 5 69 8 95.1 31.3 84.1 62.5 39.5 mg BID36 Placebo 41 1 14 17 55 18 97.6 54.8 74.5 94.4 Voclosporin 60 1 10 3 704 98.4 23.1 85.7 75.0 23.7 mg BID Voclosporin 61 2 11 7 72 9 96.8 38.984.7 77.8 39.5 mg BID 48 Placebo 37 1 5 21 42 22 97.4 80.8 88.1 95.5Voclosporin 58 0 8 3 66 3 100.0 27.3 87.9 100.0 23.7 mg BID Voclosporin61 0 5 11 66 11 100.0 68.8 92.4 100.0 39.5 mg BID

TABLE 8 Early 35% reduction in UPCR Week 48 Partial No Week 48 RemissionPartial Remission Early Positive Negative No Early No Early ReductionPredictive Predictive Week Treatment Group Early Drop Drop Early DropDrop Yes No Sensitivity Specificity Value Value 2 Placebo 13 29 13 31 2660 31.0 70.5 50.0 51.7 Voclosporin 36 25 6 18 42 43 59.0 75.0 85.7 41.923.7 mg BID Voclosporin 28 32 11 13 39 45 46.7 54.2 71.8 28.9 39.5 mgBID 4 Placebo 26 15 9 32 35 47 63.4 78.0 74.3 68.1 Voclosporin 46 13 1112 57 25 78.0 52.2 80.7 48.0 23.7 mg BID Voclosporin 43 18 13 8 56 2670.5 38.1 76.8 30.8 39.5 mg BID 6 Placebo 30 12 14 25 44 37 71.4 64.168.2 67.6 Voclosporin 47 12 9 9 56 21 79.7 50.0 83.9 42.9 23.7 mg BIDVoclosporin 47 16 14 6 61 22 74.6 30.0 77.0 27.3 39.5 mg BID 8 Placebo34 8 14 26 48 34 81.0 65.0 70.8 76.5 Voclosporin 52 8 9 10 61 18 86.752.6 85.2 55.6 23.7 mg BID Voclosporin 53 8 17 4 70 12 86.9 19.0 75.733.3 39.5 mg BID 12 Placebo 35 7 14 26 49 33 83.3 65.0 71.4 78.8Voclosporin 54 7 10 9 64 16 88.5 47.4 84.4 56.3 23.7 mg BID Voclosporin52 10 14 4 66 14 83.9 22.2 78.8 28.6 39.5 mg BID 16 Placebo 39 3 13 2652 29 92.9 66.7 75.0 89.7 Voclosporin 57 4 11 7 68 11 93.4 38.9 83.863.6 23.7 mg BID Voclosporin 55 8 13 7 68 15 87.3 35.0 80.9 46.7 39.5 mgBID 20 Placebo 38 4 15 22 53 26 90.5 59.5 71.7 84.6 Voclosporin 57 3 8 865 11 95.0 50.0 87.7 72.7 23.7 mg BID Voclosporin 56 6 15 5 71 11 90.325.0 78.9 45.5 39.5 mg BID 24 Placebo 37 3 10 25 47 28 92.5 71.4 78.789.3 Voclosporin 59 1 8 6 67 7 98.3 42.9 88.1 85.7 23.7 mg BIDVoclosporin 53 9 12 7 65 16 85.5 36.8 81.5 43.8 39.5 mg BID 26 Placebo34 5 11 19 45 24 87.2 63.3 75.6 79.2 Voclosporin 52 3 7 5 59 8 94.5 41.788.1 62.5 23.7 mg BID Voclosporin 55 6 11 5 66 11 90.2 31.3 83.3 45.539.5 mg BID 36 Placebo 41 1 12 19 53 20 97.6 61.3 77.4 95.0 Voclosporin60 1 9 4 69 5 98.4 30.8 87.0 80.0 23.7 mg BID Voclosporin 61 2 11 7 72 996.8 38.9 84.7 77.8 39.5 mg BID 48 Placebo 37 1 3 23 40 24 97.4 88.592.5 95.8 Voclosporin 58 0 7 4 65 4 100.0 36.4 89.2 100.0 23.7 mg BIDVoclosporin 61 0 4 12 65 12 100.0 75.0 93.8 100.0 39.5 mg BID

Thus it appears the 8 week or 12 week results, for example, arepredictions of ultimate outcome, and it is beneficial to stop treatmentif there was no reduction in UPCR by >15% at that time.

For completeness, Tables 9a and 9b show similar results for an 8 weekearly time point when a 25% UPCR reduction is used as a criterion andthe protocol extends for 24 or 48 weeks.

TABLE 9a Probability of attaining a CR by Proteinuria if UPCR reductionof 25% or greater is achieved at 8 weeks: #(%) of patients #(%) ofpatients # of patients # of patients who had a who had a in treatmentwith UPCR reduction of UPCR reduction of UPCR arm (number # of CRs byreduction of ≥25% who went of ≥25% who went with week 8 Proteinuria atof ≥25% at on to be a CR by on to be a CR by Group assessment) 24 weeks8 weeks UPCR at 24 weeks UPCR at 48 weeks Placebo 88 (83) 17 52 16/52(30.8) 18/52 (34.6) Low Dose 89 (80) 29 64 29/64 (45.3) 40/64 (62.5)High Dose 88 (84) 24 72 24/72 (33.3) 32/72 (44.4)

TABLE 9b Probability of attaining a CR by Proteinuria if UPCR reductionof 25% or greater is not achieved at 8 weeks: #(%) of patients #(%) ofpatients # of patients # of patients who did not have a who did not havea in treatment without UPCR reduction of UPCR reduction of UPCR arm(number # of CRs by reduction of ≥25% who went of ≥25% who went withweek 8 Proteinuria at of ≥25% at on to be a CR by on to be a CR by Groupassessment) 24 weeks 8 weeks UPCR at 24 weeks UPCR at 48 weeks Placebo88 (83) 17 31 1/31 (3.2) 3/31 (9.7)  Low Dose 89 (80) 29 16 0/16 (0.0)4/16 (25.0) High Dose 88 (84) 24 12 0/12 (0.0) 3/12 (25.0)

Another criterion for effectiveness is normalization of C3 and/or C4concentration in blood. The normal concentration of C3 is 90 mg/dl orgreater and for C4 16 mg/dl or greater. Subjects for the treatment ofthe invention generally have concentrations below these values.Normalization of C3 is defined as an increase from below 90 mg/dl toabove that level or a 25% increase from the baseline (below 90)exhibited by the subject and normalization of C4 is defined as anincrease from below 16 mg/dl to above that level or a 25% increase fromthe baseline (below 16) exhibited by the subject.

Tables 10-12 provide similar data for these criteria to the data inTables 4-9 for UPCR.

TABLE 10 Early C3 normalization Week 48 Partial No Week 48 PartialRemission Remission Positive Negative Treatment Normal- No Normal- NoNormalization Predictive Predictive Week Group ization Normalizationization Normalization Yes No Sensitivity Specificity Value Value 12Placebo 16 24 15 22 31 46 40.0 59.5 51.6 47.8 Voclosporin 23 34 8 10 3144 40.4 55.6 74.2 22.7 23.7 mg BID Voclosporin 34 28 7 10 41 38 54.858.8 82.9 26.3 39.5 mg BID 24 Placebo 17 22 16 18 33 40 43.6 52.9 51.545.0 Voclosporin 24 33 6 8 30 41 42.1 57.1 80.0 19.5 23.7 mg BIDVoclosporin 35 26 6 12 41 38 57.4 66.7 85.4 31.6 39.5 mg BID 48 Placebo15 23 14 13 29 36 39.5 48.1 51.7 36.1 Voclosporin 25 30 2 8 27 38 45.580.0 92.6 21.1 23.7 mg BID Voclosporin 34 29 7 9 41 38 54.0 56.3 82.923.7 39.5 mg BID

TABLE 11 Early C4 normalization Week 48 Partial No Week 48 PartialRemission Remission Positive Negative Treatment Normal- No Normal- NoNormalization Predictive Predictive- Week Group ization Normalizationization Normalization Yes No Sensitivity Specificity Value Value 12Placebo 15 25 19 18 34 43 37.5 48.6 44.1 41.9 Voclosporin 27 29 10 8 3737 48.2 44.4 73.0 21.6 23.7 mg BID Voclosporin 40 22 8 9 48 31 64.5 52.983.3 29.0 39.5 mg BID 24 Placebo 16 23 18 16 34 39 41.0 47.1 47.1 41.0Voclosporin 32 25 8 6 40 31 56.1 42.9 80.0 19.4 23.7 mg BID Voclosporin39 22 5 13 44 35 63.9 72.2 88.6 37.1 39.5 mg BID 48 Placebo 16 22 14 1330 35 42.1 48.1 53.3 37.1 Voclosporin 29 26 5 5 34 31 52.7 50.0 85.316.1 23.7 mg BID Voclosporin 36 27 5 11 41 38 57.1 68.8 87.8 28.9 39.5mg BID

TABLE 12 Early C3/C4 normalization Week 48 Partial No Week 48 PartialRemission Remission Positive Negative Treatment Normal- No Normal- NoNormalization Predictive Predictive Week Group ization Normalizationization Normalization Yes No Sensitivity Specificity Value Value 12Placebo 11 29 14 23 25 52 27.5 62.2 44.0 44.2 Voclosporin 20 37 6 12 2649 35.1 66.7 76.9 24.5 23.7 mg BID Voclosporin 29 33 7 10 36 43 46.858.8 80.6 23.3 39.5 mg BID 24 Placebo 12 27 14 20 26 47 30.8 58.8 46.242.6 Voclosporin 23 34 4 10 27 44 40.4 71.4 85.2 22.7 23.7 mg BIDVoclosporin 26 35 5 13 31 48 42.6 72.2 83.9 27.1 39.5 mg BID 48 Placebo10 28 10 17 20 45 26.3 63.0 50.0 37.8 Voclosporin 20 35 2 8 22 43 36.480.0 90.9 18.6 23.7 mg BID Voclosporin 27 36 5 11 32 47 42.9 68.8 84.423.4 39.5 mg BID

Tables 13-17 make similar calculations for the combined results of UPCRand C3/C4 at 12 weeks. In these tables, the data from the 12 weekdeterminations in Tables 4-8 are meshed with the data from the 12 weektime point in Table 12.

Based on the levels of sensitivity, specificity, positive predictivevalue and negative predicted value shown, decision to stop or continuetreatment is made.

TABLE 13 Early 15% reduction in UPCR or C3/C4 normalization Week 48Partial No Week 48 Partial Remission Remission Early No Early No EarlyDrop or Positive Negative Early Drop Drop or Early Drop Drop or NormalPredictive Predictive Week Treatment Group or Normal Normal or NormalNormal Yes No Sensitivity Specificity Value Value 12 Placebo 39 3 26 1265 15 92.9 31.6 60.0 80.0 Voclosporin 60 1 18 1 78 2 98.4 5.3 76.9 50.023.7 mg BID Voclosporin 60 3 16 3 76 6 95.2 15.8 78.9 50.0 39.5 mg BID24 Placebo 39 2 27 8 66 10 95.1 22.9 59.1 80.0 Voclosporin 61 0 13 1 741 100.0 7.1 82.4 100.0 23.7 mg BID Voclosporin 57 5 15 4 72 9 91.9 21.179.2 44.4 39.5 mg BID 48 Placebo 37 1 18 9 55 10 97.4 33.3 67.3 90.0Voclosporin 58 0 10 1 68 1 100.0 9.1 85.3 100.0 23.7 mg BID Voclosporin62 0 12 4 74 4 100.0 25.0 83.8 100.0 39.5 mg BID

TABLE 14 Early 20% reduction in UPCR or C3/C4 normalization Week 48Partial No Week 48 Partial Remission Remission Early No Early No EarlyDrop or Positive Negative Early Drop Drop or Early Drop Drop or NormalPredictive Predictive Week Treatment Group or Normal Normal or NormalNormal Yes No Sensitivity Specificity Value Value 12 Placebo 38 4 26 1264 16 90.5 31.6 59.4 75.0 Voclosporin 60 1 17 2 77 3 98.4 10.5 77.9 66.723.7 mg BID Voclosporin 60 3 16 3 76 6 95.2 15.8 78.9 50.0 39.5 mg BID24 Placebo 39 2 25 10 64 12 95.1 28.6 60.9 83.3 Voclosporin 61 0 13 1 741 100.0 7.1 82.4 100.0 23.7 mg BID Voclosporin 57 5 15 4 72 9 91.9 21.179.2 44.4 39.5 mg BID 48 Placebo 37 1 17 10 54 11 97.4 37.0 68.5 90.9Voclosporin 58 0 10 1 68 1 100.0 9.1 85.3 100.0 23.7 mg BID Voclosporin62 0 12 4 74 4 100.0 25.0 83.8 100.0 39.5 mg BID

TABLE 15 Early 25% reduction in UPCR or C3/C4 normalization Week 48Partial No Week 48 Partial Remission Remission Early No Early No EarlyDrop or Positive Negative Early Drop Drop or Early Drop Drop or NormalPredictive Predictive Week Treatment Group or Normal Normal or NormalNormal Yes No Sensitivity Specificity Value Value 12 Placebo 38 4 24 1462 18 90.5 36.8 61.3 77.8 Voclosporin 58 2 16 3 74 5 96.7 15.8 78.4 60.023.7 mg BID Voclosporin 60 3 16 3 76 6 95.2 15.8 78.9 50.0 39.5 mg BID24 Placebo 39 2 23 12 62 14 95.1 34.3 62.9 85.7 Voclosporin 61 0 13 1 741 100.0 7.1 82.4 100.0 23.7 mg BID Voclosporin 57 5 14 5 71 10 91.9 26.380.3 50.0 39.5 mg BID 48 Placebo 37 1 17 10 54 11 97.4 37.0 68.5 90.9Voclosporin 58 0 10 1 68 1 100.0 9.1 85.3 100.0 23.7 mg BID Voclosporin62 0 10 6 72 6 100.0 37.5 86.1 100.0 39.5 mg BID

TABLE 16 Early 30% reduction in UPCR or C3/C4 normalization Week 48Partial No Week 48 Partial Remission Remission Early No Early No EarlyDrop or Positive Negative Early Drop Drop or Early Drop Drop or NormalPredictive Predictive Week Treatment Group or Normal Normal or NormalNormal Yes No Sensitivity Specificity Value Value 12 Placebo 37 5 24 1461 19 88.1 36.8 60.7 73.7 Voclosporin 58 2 16 3 74 5 96.7 15.8 78.4 60.023.7 mg BID Voclosporin 59 4 16 3 75 7 93.7 15.8 78.7 42.9 39.5 mg BID24 Placebo 39 2 22 13 61 15 95.1 37.1 63.9 86.7 Voclosporin 61 0 13 1 741 100.0 7.1 82.4 100.0 23.7 mg BID Voclosporin 57 5 14 5 71 10 91.9 26.380.3 50.0 39.5 mg BID 48 Placebo 37 1 13 14 50 15 97.4 51.9 74.0 93.3Voclosporin 58 0 9 2 67 2 100.0 18.2 86.6 100.0 23.7 mg BID Voclosporin62 0 8 8 70 8 100.0 50.0 88.6 100.0 39.5 mg BID

TABLE 17 Early 35% reduction in UPCR or C3/C4 normalization Week 48Partial No Week 48 Partial Remission Remission Early No Early No EarlyDrop or Positive Negative Early Drop Drop or Early Drop Drop or NormalPredictive Predictive Week Treatment Group or Normal Normal or NormalNormal Yes No Sensitivity Specificity Value Value 12 Placebo 36 6 23 1559 21 85.7 39.5 61.0 71.4 Voclosporin 56 4 14 5 70 9 93.3 26.3 80.0 55.623.7 mg BID Voclosporin 57 6 16 3 73 9 90.5 15.8 78.1 33.3 39.5 mg BID24 Placebo 39 2 21 14 60 16 95.1 40.0 65.0 87.5 Voclosporin 61 0 10 4 714 100.0 28.6 85.9 100.0 23.7 mg BID Voclosporin 57 5 14 5 71 10 91.926.3 80.3 50.0 39.5 mg BID 48 Placebo 37 1 12 15 49 16 97.4 55.6 75.593.8 Voclosporin 58 0 8 3 66 3 100.0 27.3 87.9 100.0 23.7 mg BIDVoclosporin 62 0 7 9 69 9 100.0 56.3 89.9 100.0 39.5 mg BID

EXAMPLE 4 Low Dose Corticosteroid

Applicants have also found that the dosage of corticosteroid caneffectively be reduced as compared to “standard of care” as shown inTables 8 and 9, and can be reduced further to 4 mg per day or less.

TABLE 18 Standard of Care Dosing Schedule for IV methylprednisolone anddaily oral prednisone: Patients <45 kg Patients ≥45 kg Time (dailydosage) (daily dosage) Days 1-3  0.5 g IV methylprednisolone 1 g IVmethylprednisolone Days 3-112 1 mg/kg tapered down 1 mg/kg (maximum 80mg) tapered down

TABLE 19 Lowered Dosing Schedule for IV methylprednisolone and dailyoral prednisone: Patients <45 kg Patients ≥45 kg Time (daily dosage)(daily dosage) Days 1-2 0.25 g IV 0.5 g IV methylprednisolonemethylprednisolone Days 3-13 20 mg oral prednisone 25 mg oral prednisoneWeek 3 15 mg oral prednisone 20 mg oral prednisone Week 4 10 mg oralprednisone 15 mg oral prednisone Week 6 10 mg oral prednisone 10 mg oralprednisone Week 8 5 mg oral prednisone 5 mg oral prednisone Week 12 5 mgoral prednisone 5 mg oral prednisone Week 16 2.5 mg oral prednisone 2.5mg oral prednisone

1-16. (canceled)
 17. A pharmacodynamic method to treat a proteinurickidney disease which method comprises administering to a subjectdiagnosed with a proteinuric kidney disease predetermined daily dosagesof effective amounts of voclosporin over a projected treatment period toan end point, said pharmacodynamic method further comprising: (a)measuring urinary protein creatinine ratio (UPCR) of said subject at afirst time point prior to said treatment period and a second time pointoccurring prior to the end point but after the start of the treatmentperiod and determining any reduction of said UPCR between said first andsecond time points, and (b) if the UPCR of said subject fails to show areduction of at least a predetermined amount at said second time point,discontinuing administering voclosporin to the subject and continuingsaid administering if said predetermined amount of reduction is shown.18. The method of claim 17 which further comprises measuring theconcentration of C3/C4 in the blood of said subject at said first andsecond time points and determining whether the concentration of C3/C4 isnormalized at said second time point and if said normalization is found,reinstating or continuing administering voclosporin to the subject andif normalization has not occurred maintaining said discontinuing. 19.The method of claim 17 or 18 wherein said method further includesadministering to said subject an effective amount of mycophenolatemofetil (MMF).
 20. The method of claim 17 or 18 which further includesadministering to said subject an effective amount of a corticosteroid.21. The method of claim 17 or 18 wherein said predetermined daily dosageis 39.5 mg voclosporin BID or 31.6 mg voclosporin BID or 23.7 mgvoclosporin BID or 15.8 mg voclosporin BID or 7.9 mg voclosporin BID.22. A method to treat a proteinuric kidney disease which methodcomprises administering to a subject diagnosed with lupus nephritis apredetermined daily dosage of effective amounts of voclosporin over aprojected treatment period of at least 8 weeks, wherein said effectiveamount is 15.8 mg BID or 7.9 mg voclosporin BID.